Stable, concentrated radionuclide complex solutions

ABSTRACT

The present invention relates to radionuclide complex solutions of high concentration and of high chemical stability, that allows their use as drug product for diagnostic and/or therapeutic purposes. The stability of the drug product is achieved by at least one stabilizer against radiolytic degradation. The use of two stabilizers introduced during the manufacturing process at different stages was found to be of particular advantage.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/175,261 filed Oct. 30, 2018, which is a continuation-in-partapplication of U.S. application Ser. No. 16/140,962 filed Sep. 25, 2018,which is a continuation-in-part of U.S. application Ser. No. 16/045,484filed Jul. 25, 2018 and claims priority to, and the benefit ofInternational Application Nos. PCT/IB2018/055575 filed Jul. 25, 2018 andPCT/IB2018/057415 filed Sep. 25, 2018, the contents of each of which arehereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to radionuclide complex solutions of highconcentration and of high chemical and radiochemical stability, thatallows their use as commercial drug product for diagnostic and/ortherapeutic purposes.

BACKGROUND OF THE INVENTION

The concept of targeted drug delivery is based on cell receptors whichare overexpressed in the target cell in contrast to thenot-to-be-targeted cells. If a drug has a binding site to thoseoverexpressed cell receptors it allows the delivery of the drug afterits systemic administration in high concentration to those target cellswhile leaving other cells, which are not of interested, unaffected. Forexample, if tumor cells are characterized by an overexpression of aspecific cell receptor, a drug with binding affinity to said receptorwill after intravenous infusion accumulate in high concentration in thetumor tissue while leaving the normal tissue unaffected. This targeteddrug delivery concept has also been used in radiomedicine to deliverradionuclides selectively to the target cells for diagnostic ortherapeutic purposes.

For this radiomedicinal application the target cell receptor bindingmoiety is typically linked to a chelating agent which is able to form astrong complex with the metal ions of a radionuclide. Thisradiopharmaceutical drug is then delivered to the target cell and thedecay of the radionuclide is then releasing high energy electrons,positrons or alpha particles as well as gamma rays at the target site.

One technical problem with those radiopharmaceutical drug products isthat the decay of the radionuclide occurs constantly, e.g. also duringthe manufacturing and during storage of the drug product, and thereleased high energy emissions induce the cleavage of the chemical bondsof the molecules which form part of the drug product. This is oftenreferred to as radiolysis or radiolytic degradation. The radiolyticdegradation of the receptor binding moiety of the drug may lead to adecrease in its efficacy to act as a diagnostic and/or therapeutic.

The poor stability of those radiopharmaceutical drug products and theirlack of any significant shelf-life required that those drugs have so farto be manufactured as an individual patient's dose unit in thelaboratories at the hospital and administered immediately to the patientwho had to be present at that hospital already awaiting the radiologicaltreatment. To facilitate such drug preparation in the hospitallaboratories, “cold” (i.e. non-radioactive) freeze-dried kits have beendeveloped which comprise the cell receptor binding moiety linked to achelating agent without the radionuclide. The freeze-dried content ofthose kit vials is then to be reconstituted with a solution of theradionuclide short before administration (Das et al. J Radioanal NuclChem 2014, 299, 1389-1398; Das et al. Current Radiopharmaceuticals 2014,7, 12-19; Luna-Gutierrez et al. J Radioanal Nucl Chem 2017, 314,2181-2188). However, those kits are not “ready-to-use” as they requirethe reconstitution step and in addition further processing steps (e.g.applying heat for the complexation reaction) as well as purification andsterilization steps before the drug can be finally administered.

To reduce radiolysis of radiopharmaceutical drug products and thusimprove stability, various strategies have been explored with more orless success: The drug product may be stored at low temperatures, orproduced in high dilution, or stabilizers may be added.

Adding stabilizers however may be problematic as those chemicals mayhave a negative impact on the complexation of the radionuclide into thechelating agent or may have a limited solubility and precipitate fromthe solution. Ethanol has been reported as stabilizer against radiolysis(WO 2008/009444). While ethanol might not have a negative impact on thecomplexation or a solubility issue, higher amounts of ethanol in aninfusion solution may be physiologically problematic and may have anegative impact on the tolerability of the drug product.

Producing the drug product in high dilution has the disadvantage thatlarge volumes of infusion solutions need to be administered to patients.For the convenience of patients and for drug tolerability reasons itwould be highly desirable to provide the radiopharmaceutical drugproduct in a high concentration. Those highly concentrated solutionshowever are in particular prone to radiolysis. Therefore, there arecontradictory positions between, on the one hand, avoiding radiolysis bydilution of the drug product but, on the other hand, avoiding patientdiscomfort during treatment by providing a concentrated drug solution.In Mathur et al. Cancer Biotherapy and Radiopharmaceuticals, 2017,32(7), 266-273 a product of high concentration has been reported andclaimed being ready-to-use. However, that composition may be problematicwith respect to tolerability as it contains high amounts of ethanol.

It remains therefore a challenge to design a ready-to-useradiopharmaceutical drug product which can be produced at commercialscale and delivered as a sufficiently stable and sterile solution in ahigh concentration which leads to a convenient small infusion volume forpatients and which has a composition of high physiological tolerability(e.g. a composition which does not contain ethanol).

SUMMARY OF THE INVENTION

The present inventors have now found a way to design and produce ahighly concentrated radionuclide complex solution which is chemicallyand radiochemically very stable even if stored at ambient or short termelevated temperatures so that it can be produced on commercial scale andsupplied as ready-to-use radiopharmaceutical product.

The present invention is provided in various aspects as outlined in thefollowing:

A pharmaceutical aqueous solution comprising

-   -   (a) a complex formed by        -   (ai) a radionuclide, and        -   (aii) a cell receptor binding organic moiety linked to a            chelating agent; and    -   (b) at least one stabilizer against radiolytic degradation;    -   wherein        said radionuclide is present in a concentration that it provides        a volumetric radioactivity of at least 100 MBq/mL, preferably of        at least 250 MBq/mL.

Said stabilizer(s), component (b), is (are) present in a totalconcentration of at least 0.2 mg/mL, preferably at least 0.5 mg/mL, morepreferably at least 1.0 mg/mL, even more preferably at least 2.7 mg/mL.

A pharmaceutical aqueous solution, comprising

-   -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lutetium (Lu-177), present in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) the chelating agent linked somatostatin receptor            binding organic moiety DOTA-TATE (oxodotreotide) or DOTA-TOC            (edotreotide);    -   (bi) gentisic acid or a salt thereof as the first stabilizer        against radiolytic degradation present in a concentration of        from 0.5 to 1 mg/mL;    -   (bii) ascorbic acid or a salt thereof as the second stabilizer        against radiolytic degradation present in a concentration of        from 2.0 to 5.0 mg/mL.

-   A process for manufacturing said pharmaceutical aqueous solution as    defined above, comprising the process steps:    -   (1) Forming a complex of the radionuclide and the chelating        agent linked cell receptor binding organic moiety by        -   (1.1) preparing an aqueous solution comprising the            radionuclide;        -   (1.2) preparing an aqueous solution comprising the chelating            agent linked cell receptor binding organic moiety, a first            stabilizer, optionally a second stabilizer; and        -   (1.3) mixing the solutions obtained in steps (1.1) and (1.2)            and heating the resulting mixture;    -   (2) Diluting the complex solution obtained by step (1) by        -   (2.1) preparing an aqueous dilution solution optionally            comprising a second stabilizer; and        -   (2.2.) mixing the complex solution obtained by step (1) with            the dilution solution obtained by the step (2.1).

The present invention provide the following advantages:

The high concentration allows administering a high dose within a shorttime frame. E.g. in the case of ¹⁷⁷Lu-DOTA-TATE, the high dose of 7.4GBq can be provided in a small volume of 20.5 to 25.0 mL which allowsthe IV infusion administration to be completed within about 20 to 30minutes.

The use of suitable stabilizer(s), according to the present invention asdescribed, herein ensures high stability, at least 95%, 96%, 97%, 98%,99% or 100% chemical stability with respect to the chemical purity forthe cell receptor-binding molecule after 72 hours at 25° C., even ifthis molecule is a sensitive peptide molecule. E.g. for DOTA-TATE 100%chemical purity were found after 72 hours at 25° C. and even after 48hours at 32° C. were found. Even under short term elevated temperatureconditions (32° C. for 12 h and 25° for 60 h) such high stability wasfound with respect to chemical purity.

Further, the use of suitable stabilizer(s), according to the presentinvention as described, herein ensures high stability, at least 95%radiochemical stability with respect to the radiochemical purityradionuclide complex. E.g. for ¹⁷⁷Lu-DOTA-TATE at least 95%radiochemical purity were found after 72 hours at 25° C. Even undershort term elevated temperature conditions (32° C. for 12 h and 25° for60 h) such high stability was found with respect to radiochemicalpurity.

While sufficient stability may be achieved already with one singlestabilizer, the use of two stabilizers has been found to be ofparticular suitability in stabilizing sensitive radiopharmaceuticalsolutions. In particular, the presence of one stabilizer during complexformation and another stabilizer added after the complex formation is ofadvantage as it ensures that already during the complexation reaction,the cell receptor-binding molecule is protected against radiolysis andthe other stabilizer enhances the protecting effect for the shelf-lifeperiod. Further, by this sequential application of the two stabilizersit is ensured, that during complexation only a relatively small amountof stabilizer is present (which minimizes the potential interference ofthat stabilizer with the complexation reaction) and after complexation alarge amount of a stabilizer combination is present (which strengthensthe protective power of the stabilizers for the following drug productstorage time period).

This sequential application of two stabilizers also reduces the overallthermal stress of those stabilizers as one of them is not present whenthe complexation reaction, which involves high temperatures, takesplace.

Further, particularly the use of two different stabilizers isadvantageous as this combination is more efficacious in reacting to thevarious different radicals possibly formed by the radiolysis of the cellreceptor binding molecule than only one single stabilizer can do.

The composition of the radiopharmaceutical solution does not require thepresence of ethanol. The solution is sufficiently stable withoutethanol. The absence of ethanol is of advantage with respect to thephysiological tolerability of the solution.

A shelf-life of at least 3 days is required to allow aradiopharmaceutical drug product to be manufactured from a centralizedpharmaceutical production site and to commercialize it as a ready-to-usedrug product.

Therefore, due to the high stability (72 h at 25° C.) the presentinvention allows centralized pharmaceutical production at highestquality standards (e.g. cGMP) and at industrial scale, e.g. at 74 GBq or148 GBq batch size which provides the drug product in numerous doseunits, e.g. enough dose units for the treatment of 10 to 20 patients atthe same time.

Further, due to the high stability, there is sufficient time for thepresent invention to be shipped from a centralized pharmaceuticalproduction site to remote clinical centers.

Even further, due to the high stability, the present invention can beprovided as a ready-to-use infusion solution which can be immediatelyadministered to the patient without a need for the clinical staff toperform any preparatory work before administration.

The present invention of particular suitability for the somatotatinreceptor binding peptides, here in particular for the very sensitivesomatostatin analogues octreotide and octreotate which are in particularprone to degradation reactions. Further, the present invention ofparticular suitability for the radionuclide Lutetium-177 with itsspecific radioactivity characteristics.

DETAILED DESCRIPTION OF THE INVENTION

Herein after, the present invention is described in further detail andis exemplified.

In general, the present invention is concerned about a pharmaceuticalaqueous solution, in particular a radiopharmaceutical aqueous solution.The solution is for intravenous (IV) use/application/administration. Thesolution is stable, concentrated, and ready-to-use.

The stability of the solution ascertained by the use of stabilizersagainst radiolytic degradation.

In general, the stabilizers used in accordance with the presentinventions may be selected from gentisic acid (2,5-dihydroxybenzoicacid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) orsalts thereof (e.g. sodium ascorbate), methionine, histidine, melatonin,ethanol, and Se-methionine. Preferred stabilizers are selected fromgentisic acid or salts thereof and ascorbic acid or salts thereof.

Ethanol is considered as less preferred stabilizer due to tolerabilityissues associated with it if present in higher concentrations. Ethanolshould be ideally avoided in the solutions of the present invention (inother words: free of ethanol), at least the amount of ethanol in thesolutions of the present invention should be limited, e.g. less than 5%,preferably less than 2%, more preferably less than 1% in the finalsolution which is foreseen to be injected/infused. Even more preferably,the solution is free of ethanol.

In accordance with the present invention the following embodiments areprovided:

-   1. A pharmaceutical aqueous solution comprising    -   (a) a complex formed by        -   (ai) a radionuclide, and        -   (aii) a cell receptor binding organic moiety linked to a            chelating agent; and    -   (b) at least one stabilizer against radiolytic degradation;    -   wherein    -   said radionuclide is present in a concentration that it provides        a volumetric radioactivity of at least 100 MBq/mL, preferably of        at least 250 MBq/mL.-   2. The pharmaceutical aqueous solution according to embodiment 1,    -   wherein said stabilizer(s), component (b), is (are) present in a        total concentration of at least 0.2 mg/mL, preferably at least        0.5 mg/mL, more preferably at least 1.0 mg/mL, even more        preferably at least 2.7 mg/mL.-   3. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein said radionuclide is present in a    concentration that it provides a volumetric radioactivity of from    100 to 1000 MBq/mL, preferably from 250 to 500 MBq/m L.-   4. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein said stabilizer(s) is (are) present    in a total concentration of from 0.2 to 20.0 mg/mL, preferably from    0.5 to 10.0 mg/mL, more preferably from 1.0 to 5.0 mg/mL, even more    preferably from 2.7 to 4.1 mg/mL.-   5. The pharmaceutical aqueous solution according to any one of the    preceding embodiments,    -   wherein the component (b) is only one stabilizers against        radiolytic degradation, i.e. only a first stabilizer.-   6. The pharmaceutical aqueous solution according to any one of the    preceding embodiments,    -   wherein the component (b) are at least two stabilizers against        radiolytic degradation, i.e. at least a first and a second        stabilizer, preferably only two stabilizers, i.e. only a first        and a second stabilizer.-   7. The pharmaceutical aqueous solution according to any one of the    embodiments 5 to 6, wherein the first stabilizer is present in a    concentration of from 0.2 to 5 mg/mL, preferably from 0.5 to 5    mg/mL, more preferably from 0.5 to 2 mg/mL, even more preferably    from 0.5 to 1 mg/mL, even more preferably from 0.5 to 0.7 mg/mL.-   8. The pharmaceutical aqueous solution according to embodiment 6 or    7, wherein the second stabilizer is present in a concentration of    from 0.5 to 10 mg/mL, more preferably from 1.0 to 8.0 mg/mL, even    more preferably from 2.0 to 5.0 mg/mL, even more preferably from 2.2    to 3.4 mg/mL.-   9. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein the stabilizer(s) is (are) selected    from gentisic acid (2,5-dihydroxybenzoic acid) or salts thereof,    ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g.    sodium ascorbate), methionine, histidine, melatonin, ethanol, and    Se-methionine, preferably selected from gentisic acid or salts    thereof and ascorbic acid or salts thereof.-   10. The pharmaceutical aqueous solution according to any one of the    embodiments 5 to 9, wherein the first stabilizer is selected from    gentisic acid and ascorbic acid, preferably the first stabilizer is    gentisic acid.-   11. The pharmaceutical aqueous solution according to any one of the    embodiments 6 to 10, wherein the second stabilizer is selected from    gentisic acid and ascorbic acid, preferably the second stabilizer is    ascorbic acid.-   12. The pharmaceutical aqueous solution according to any one of the    embodiments 6 to 8, wherein the first stabilizer is gentisic acid or    a salt thereof and the second stabilizer is ascorbic acid or a salt    thereof, and the ratio of the concentration (in mg/mL) of the first    stabilizer to the concentration (in mg/mL) of the second stabilizer    is from 1:3 to 1:7, preferably from 1:4 to 1:5.-   13. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein the radionuclide is selected from    ¹⁷⁷Lu, ⁶⁸Ga, ¹⁸F, ^(99m)Tc, ²¹¹At, ⁸²Rb, ¹⁶⁶Ho, ²²⁵Ac, ¹¹¹In, ¹²³I,    ¹³¹I, ⁸⁹Zr, ⁹⁰Y, preferably selected from ¹⁷⁷Lu and ⁶⁸Ga, more    preferably is ¹⁷⁷Lu.-   14. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein the cell receptor binding moiety is a    somatostatin receptor binding peptide, preferably said somatostatin    receptor binding peptide is selected from octreotide, octreotate,    lanreotide, vapreotide and pasireotide, preferably selected from    octreotide and octreotate.-   15. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein the chelating agent is selected from    DOTA, DTPA, NTA, EDTA, DO3A, NOC and NOTA, preferably is DOTA.-   16. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein the cell receptor binding moiety and    the chelating agent form together molecules selected from DOTA-OC,    DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide),    DOTA-LAN, and DOTA-VAP, preferably selected from DOTA-TOC and    DOTA-TATE, more preferably is DOTA-TATE.-   17. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein the radionuclide, the cell receptor    binding moiety and the chelating agent form together the complex    ¹⁷⁷Lu-DOTA-TOC (¹⁷⁷Lu-edotreotide) or ¹⁷⁷Lu-DOTA-TATE    (¹⁷⁷Lu-oxodotreotide), preferably ¹⁷⁷Lu-DOTA-TATE.-   18. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, further comprising a buffer, preferably said    buffer is an acetate buffer, preferably in an amount to result in a    concentration of from 0.3 to 0.7 mg/mL (preferably about 0.48 mg/mL)    acetic acid and from 0.4 to 0.9 mg/mL (preferably about 0.66 mg/mL)    sodium acetate.-   19. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, further comprising a sequestering agent,    preferably said sequestering agent is diethylentriaminepentaacetic    acid (DTPA) or a salt thereof, preferably in an amount to result in    a concentration of from 0.01 to 0.10 mg/mL (preferably about 0.05    mg/mL).-   20. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, which has a shelf life of at least 24    hours (h) at ≤25° C., at least 48 h at ≤25° C., at least 72 h at    ≤25° C., of from 24 h to 120 h at ≤25° C., from 24 h to 96 h at ≤25°    C., from 24 h to 84 h at ≤25° C., from 24 h to 72 h at ≤25° C., in    particular has a shelf life of 72 h at ≤25° C.-   21. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, wherein said solution is produced at    commercial scale manufacturing, in particular is produced at a batch    size of at least 20 GBq, at least 50 GBq, or at least 70 GBq.-   22a. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, which is ready-to-use.-   22b. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, which is for commercial use.-   23. A pharmaceutical aqueous solution, comprising    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lutetium (Lu-177), present in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) the chelating agent linked somatostatin receptor            binging organic moiety DOTA-TATE (oxodotreotide) or DOTA-TOC            (edotreotide);    -   (bi) gentisic acid or a salt thereof as the first stabilizer        against radiolytic degradation present in a concentration of        from 0.5 to 1 mg/mL;    -   (bii) ascorbic acid or a salt thereof as the second stabilizer        against radiolytic degradation present in a concentration of        from 2.0 to 5.0 mg/mL.-   24. The pharmaceutical aqueous solution according to embodiment 23,    further comprising: (c) Diethylentriaminepentaacetic acid (DTPA) or    a salt thereof in a concentration of from 0.01 to 0.10 mg/mL.-   25. The pharmaceutical aqueous solution according to embodiments 23    or 24, further comprising:    -   (d) acetic acid in a concentration of from 0.3 to 0.7 mg/mL and        sodium acetate in a concentration from 0.4 to 0.9 mg/mL.-   26. The pharmaceutical aqueous solution according to any one of the    preceding embodiments wherein the stabilizer(s) is (are) present in    the solution during the complex formation of components (ai) and    (aii).-   27. The pharmaceutical aqueous solution according to any one of    embodiments 5 to 26 wherein only the first stabilizer is present    during the complex formation of components (ai) and (aii),    preferably in an amount to result in a concentration of from 0.5 to    5 mg/mL, more preferably from 0.5 to 2 mg/mL, even more preferably    from 0.5 to 1 mg/mL, even more preferably from 0.5 to 0.7 mg/mL, in    the final solution.-   28. The pharmaceutical aqueous solution according to any one of    embodiments 6 to 27 wherein a part of the amount of the second    stabilizer is already present in the solution during the complex    formation of components (ai) and (aii) and another part of the    amount of the second stabilizer is added after the complex formation    of components (ai) and (aii).-   29. The pharmaceutical aqueous solution according to any one of    embodiments 6 to 28 wherein the second stabilizer is added after the    complex formation of components (ai) and (aii).-   30. The pharmaceutical aqueous solution according to embodiment 6 or    29 wherein the second stabilizer is added after the complex    formation of components (ai) and (aii), preferably in an amount to    result in a concentration of from 0.5 to 10 mg/mL, more preferably    from 1.0 to 8.0 mg/mL, even more preferably from 2.0 to 5.0 mg/mL,    even more preferably from 2.2 to 3.4 mg/mL, in the final solution.-   31. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, further comprising a sequestering agent,    added after the complex formation of components (ai) and (aii), for    removing any uncomplexed Lu, preferably said sequestering agent is    diethylentriaminepentaacetic acid (DTPA) or a salt thereof,    preferably in an amount to result in a concentration of from 0.01 to    0.10 mg/mL (preferably about 0.05 mg/mL) in the final solution.-   32. A process for manufacturing the pharmaceutical aqueous solution    as defined in any one of the preceding embodiments, comprising the    process steps:    -   (1) Forming a complex of the radionuclide and the chelating        agent linked cell receptor binding organic moiety by        -   (1.1) preparing an aqueous solution comprising the            radionuclide;        -   (1.2) preparing an aqueous solution comprising the chelating            agent linked cell receptor binding organic moiety, a first            stabilizer, optionally a second stabilizer; and        -   (1.3) mixing the solutions obtained in steps (1.1) and (1.2)            and heating the resulting mixture;    -   (2) Diluting the complex solution obtained by step (1) by        -   (2.1) preparing an aqueous dilution solution optionally            comprising a second stabilizer; and        -   (2.2.) mixing the complex solution obtained by step (1) with            the dilution solution obtained by the step (2.1).-   33. The process according to embodiment 32 wherein only the first    stabilizer is present during the step (1.3), preferably in an amount    to result in a concentration of from 0.5 to 5 mg/mL, more preferably    from 0.5 to 2 mg/mL, even more preferably from 0.5 to 1 mg/mL, even    more preferably from 0.5 to 0.7 mg/mL, in the final solution.-   34. The process according to any one of embodiments 32 to 33 wherein    a part of the amount of the second stabilizer is already present in    the solution during the step (1.3) and another part of the amount of    the second stabilizer is added, after the step (1.3), in step (2.1).-   35. The pharmaceutical aqueous solution according to any one of    embodiments 32 to 34 wherein the second stabilizer is added, after    the step (1.3), in step (2.1).-   36. The pharmaceutical aqueous solution according to any one of    embodiments 32 to 35 wherein the second stabilizer is added, after    the step (1.3), in step (2.1), preferably in an amount to result in    a concentration of from 0.5 to 10 mg/mL, more preferably from 1.0 to    8.0 mg/mL, even more preferably from 2.0 to 5.0 mg/mL, even more    preferably from 2.2 to 3.4 mg/mL, in the final solution.-   37. The process according any one of embodiments 32 to 36, wherein    the solution of step (1.2) further comprises a buffer, preferably an    acetate buffer.-   38. The process according to any one of embodiments 32 to 37,    wherein in step (1.3) the resulting mixture is heated to a    temperature of from 70 to 99° C., preferably from 90 to 98° C., for    from 2 to 59 min.-   39. The process according to any one of embodiments 32 to 38,    wherein the solution of step (2.1) further comprises    diethylentriaminepentaacetic acid (DTPA) or a salt thereof.-   40. The process according to any one of embodiments 32 to 39,    further comprising the process steps:    -   (3) Filtering the solution obtained by step (2) through 0.2 μm:    -   (4) Dispensing the filtered solution obtained by step (3) into        dose unit containers in a volume required to deliver the        radioactive dose of from 5.0 to 10 MBq, preferably from 7.0 to        8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more        preferably from 7.4-7.5 MBq, preferably said volume is from 10        to 50 mL, more preferably from 15 to 30 mL, even more preferably        from 20 to 25 mL.-   41. The process according to any one of embodiments 32 to 40,    wherein the solution of step (1.1) comprises LuCl₃ and HCl.-   42. The process according to any one of embodiments 32 to 41,    wherein the solution of step (1.2) comprises ¹⁷⁷Lu-DOTA-TATE or    ¹⁷⁷Lu-DOTA-TOC, gentisic acid, acetic acid, and sodium acetate.-   43. The process according to any one of embodiments 32 to 42,    wherein the solution of step (2.1) comprises DTPA, and ascorbic    acid.-   44. The process according to any one of embodiments 32 to 43,    wherein the dose unit containers in step (4) are stoppered vials,    enclosed within a lead container.-   45. The pharmaceutical aqueous solution obtained (or obtainable) by    the process as defined in any one of the embodiments 32 to 44.

Further embodiments of the present invention are described in thefollowing as “E embodiments”:

-   E1. A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177), and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA; and    -   (b) at least two different stabilizers against radiolytic        degradation;    -   wherein        -   said radionuclide is present in a concentration that it            provides a volumetric radioactivity of from 250 to 500            MBq/mL; and        -   said stabilizers are present in a total concentration of            from 0.2 to 20.0 mg/mL.    -   The “complex formed by” may be alternatively worded: “complex        of”.    -   The “different” in “two different stabilizers” refers to a        difference in the chemical entity of such stabilizers. “Two        different stabilizers” has the meaning that the two stabilizers        are different chemical entities, e.g. gentisic acid and ascorbic        acid are two different stabilizers. “at least two” means two or        more, however, preferably that just two stabilizers are present        (not three or more). It is further preferred that ethanol is not        one of the two stabilizers.-   E2. The pharmaceutical aqueous solution according to embodiment E1,    -   wherein said component (b) comprises the stabilizers:        -   (bi) gentisic acid or a salt thereof; and        -   (bii) ascorbic acid or a salt thereof.-   E3. The pharmaceutical aqueous solution according to embodiment E2,    -   wherein        -   (bi) gentisic acid is present in a concentration of from 0.5            to 2 mg/mL, preferably from 0.5 to 1 mg/mL; and        -   (bii) ascorbic acid is present in a concentration of from            2.0 to 5.0 mg/mL.

In a particular embodiment the present invention provides:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA; and    -   (b) the stabilizers against radiolytic degradation        -   (bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL            and        -   (bii) ascorbic acid in a concentration of from 2.0 to 5.0            mg/mL.

-   E4. The pharmaceutical aqueous solution according to embodiment E3,    further comprising:    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL.

-   E5. The pharmaceutical aqueous solution according to embodiments E3    or E4, further comprising:    -   (d) an acetate buffer composed of:    -   (di) acetic acid in a concentration of from 0.3 to 0.7 mg/mL;        and    -   (dii) sodium acetate in a concentration from 0.4 to 0.9 mg/mL;

preferably said acetate buffer provides for a pH of from 4.5 to 6.0,preferably from 4.7 to 6.0, more preferably from 5.0 to 6.0, even morepreferably from 5.0 to 5.5.

In a particular embodiment the present invention provides:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) at least two stabilizers against radiolytic degradation        comprising (bi) gentisic acid in a concentration of from 0.5 to        1 mg/mL and (bii) ascorbic acid in a concentration of from 2.0        to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;    -   preferably said acetate buffer provides for a pH of from 5.0 to        5.5.

In a particular embodiment the present invention provides:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) stabilizers against radiolytic degradation consisting of        (bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL and        (bii) ascorbic acid in a concentration of from 2.0 to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;            preferably said acetate buffer provides for a pH of from 5.0            to 5.5.    -   The herein indicated pH values are the pH values of the final        solution. However, it can also be the pH during manufacturing of        the solution, e.g. the pH during the complex formation.

-   E6. The pharmaceutical aqueous solution according to any one of the    embodiments E1 to E5 wherein at least one of the stabilizers is    present during the complex formation of components (ai) and (aii)    and at least one of the stabilizers is added after the complex    formation of components (ai) and (aii).

-   E7. The pharmaceutical aqueous solution according to any one of the    embodiments E1 to E5 wherein at least gentisic acid is present    during the complex formation of components (ai) and (aii) and at    least ascorbic acid is added after the complex formation of    components (ai) and (aii).

-   E8. The pharmaceutical aqueous solution according to any one of the    embodiments E1 to E5 wherein the only stabilizer present during the    complex formation of components (ai) and (aii) is gentisic acid and    the only stabilizer added after the complex formation of components    (ai) and (aii) is ascorbic acid.

In a particular embodiment the present invention provides:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA; and    -   (b) the stabilizers against radiolytic degradation        -   (bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL            (in the final solution) and        -   (bii) ascorbic acid in a concentration of from 2.0 to 5.0            mg/mL (in the final solution);    -   wherein gentisic acid is present during the complex formation of        components (ai) and (aii) and ascorbic acid added after the        complex formation of components (ai) and (aii).

In a particular embodiment the present invention is defined in thefollowing:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) at least two stabilizers against radiolytic degradation        comprising (bi) gentisic acid in a concentration of from 0.5 to        1 mg/mL and (bii) ascorbic acid in a concentration of from 2.0        to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;    -   preferably said acetate buffer provides for a pH of from 5.0 to        5.5;    -   wherein gentisic acid is present during the complex formation of        components (ai) and (aii) and ascorbic acid added after the        complex formation of components (ai) and (aii).

In a particular embodiment the present invention is defined in thefollowing:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) stabilizers against radiolytic degradation consisting of        (bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL and        (bii) ascorbic acid in a concentration of from 2.0 to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;    -   preferably said acetate buffer provides for a pH of from 5.0 to        5.5;    -   wherein gentisic acid is present during the complex formation of        components (ai) and (aii) and ascorbic acid added after the        complex formation of components (ai) and (aii).

-   E9. The pharmaceutical aqueous solution according to any one of the    embodiments E6 to E8 wherein that/those stabilizer/stabilizers which    is/are present during the complex formation of components (ai) and    (aii) is/are present during the complex formulation in a total    concentration of from 15 to 50 mg/mL, preferably from 20 to 40    mg/mL.

-   E10. The pharmaceutical aqueous solution according to embodiment E9    wherein the only stabilizer present during the complex formation of    components (ai) and (aii) is gentisic acid and is present during the    complex formulation in a concentration of from 20 to 40 mg/mL,    preferably from 25 to 35 mg/mL.

In a particular embodiment the present invention is defined in thefollowing:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) at least two stabilizers against radiolytic degradation        comprising (bi) gentisic acid in a concentration of from 0.5 to        1 mg/mL and (bii) ascorbic acid in a concentration of from 2.0        to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;    -   preferably said acetate buffer provides for a pH of from 5.0 to        5.5;    -   wherein gentisic acid is present during the complex formation of        components (ai) and (aii) and ascorbic acid added after the        complex formation of components (ai) and (aii); and    -   wherein the only stabilizer present during the complex formation        of components (ai) and (aii) is gentisic acid and is present        during the complex formulation in a concentration of from 20 to        40 mg/mL, preferably from 25 to 35 mg/mL.

In a particular embodiment the present invention is defined in thefollowing:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL, and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) stabilizers against radiolytic degradation consisting of        (bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL and        (bii) ascorbic acid in a concentration of from 2.0 to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;    -   preferably said acetate buffer provides for a pH of from 5.0 to        5.5;    -   wherein gentisic acid is present during the complex formation of        components (ai) and (aii) and ascorbic acid added after the        complex formation of components (ai) and (aii); and    -   wherein the only stabilizer present during the complex formation        of components (ai) and (aii) is gentisic acid and is present        during the complex formulation in a concentration of from 20 to        40 mg/mL, preferably from 25 to 35 mg/mL.

Embodiments E6 to E10 may be alternatively defined by the followingwording:

-   -   E6. The pharmaceutical aqueous solution according to any one of        the embodiments E1 to E5 produced by having at least one of the        stabilizers present during the complex formation of components        (ai) and (aii) and at least one of the stabilizers added after        the complex formation of components (ai) and (aii).    -   E7. The pharmaceutical aqueous solution according to any one of        the embodiments E1 to E5 produced by having at least gentisic        acid present during the complex formation of components (ai) and        (aii) and at least ascorbic acid added after the complex        formation of components (ai) and (aii).    -   E8. The pharmaceutical aqueous solution according to any one of        the embodiments E1 to E5 produced by having gentisic acid as the        only stabilizer present during the complex formation of        components (ai) and (aii) ascorbic acid as the only stabilizer        added after the complex formation of components (ai) and (aii).    -   E9. The pharmaceutical aqueous solution according to any one of        the embodiments E6 to E8 produced by having that/those        stabilizer/stabilizers present during the complex formation of        components (ai) and (aii) present during the complex formation        in a total concentration of from 15 to 50 mg/mL, preferably from        20 to 40 mg/mL.    -   E10. The pharmaceutical aqueous solution according to embodiment        E9 produced by having gentisic acid as the only stabilizer        present during the complex formation of components (ai) and        (aii) and present during the complex formulation in a        concentration of from 20 to 40 mg/mL, preferably from 25 to 35        mg/mL.

In the embodiments of the present invention, in particular inembodiments E9 and E10, the radionuclide may be present during thecomplex formation in a concentration that it provides a volumetricradioactivity of up to 20 GBq/mL, preferably up to 15 GBq/mL, or from 5to 20 GBq/mL, preferably from 10 to 20 GBq/mL, more preferably from 10to 15 GBq/mL.

In a particular embodiment the present invention is defined in thefollowing:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL (in the final solution), and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) at least two stabilizers against radiolytic degradation        comprising (bi) gentisic acid in a concentration of from 0.5 to        1 mg/mL and (bii) ascorbic acid in a concentration of from 2.0        to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;    -   preferably said acetate buffer provides for a pH of from 5.0 to        5.5;    -   wherein gentisic acid is present during the complex formation of        components (ai) and (aii) and ascorbic acid added after the        complex formation of components (ai) and (aii); and    -   wherein the only stabilizer present during the complex formation        of components (ai) and (aii) is gentisic acid and is present        during the complex formulation in a concentration of from 20 to        40 mg/mL;    -   and wherein the radionuclide is present during the complex        formation in a concentration that it provides a volumetric        radioactivity of from 10 to 20 GBq/mL.

In a particular embodiment the present invention is defined in thefollowing:

-   -   A pharmaceutical aqueous solution comprising:    -   (a) a complex formed by        -   (ai) the radionuclide ¹⁷⁷Lu (Lutetium-177) in a            concentration that it provides a volumetric radioactivity of            from 250 to 500 MBq/mL (in the final solution), and        -   (aii) a somatostatin receptor binding peptide linked to the            chelating agent DOTA;    -   (b) stabilizers against radiolytic degradation consisting of        (bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL and        (bii) ascorbic acid in a concentration of from 2.0 to 5.0 mg/mL;    -   (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof        in a concentration of from 0.01 to 0.10 mg/mL; and    -   (d) an acetate buffer composed of:        -   (di) acetic acid in a concentration of from 0.3 to 0.7            mg/mL; and        -   (dii) sodium acetate in a concentration from 0.4 to 0.9            mg/mL;    -   preferably said acetate buffer provides for a pH of from 5.0 to        5.5;    -   wherein gentisic acid is present during the complex formation of        components (ai) and (aii) and ascorbic acid added after the        complex formation of components (ai) and (aii); and    -   wherein the only stabilizer present during the complex formation        of components (ai) and (aii) is gentisic acid and is present        during the complex formulation in a concentration of from 20 to        40 mg/mL;    -   and wherein the radionuclide is present during the complex        formation in a concentration that it provides a volumetric        radioactivity of from 10 to 20 GBq/mL.

-   E11. The pharmaceutical aqueous solution according to any one of the    preceding E embodiments, which has a shelf life of at least 72 h    when stored at ≤25° C., in particular at least 72 h when stored at    25° C.    -   “Shelf life” has herein its general meaning in the context of        pharmaceutical products. The shelf life is the length of time        that a pharmaceutical product may be stored while its product        characteristics still comply with the product specification as        defined during drug development and agreed by health        authorities.

-   E12. The pharmaceutical aqueous solution according to any one of the    preceding E embodiments, for which the radiochemical purity    (determined by HPLC) is maintained at 95% for at least 72 h when    stored at 25° C.

-   E13. The pharmaceutical aqueous solution according to any one of the    preceding E embodiments, wherein said solution is produced at    commercial manufacturing scale, in particular is produced at a batch    size of at least 20 GBq, at least 50 GBq, or at least 70 GBq.

-   E14. The pharmaceutical aqueous solution according to any one of the    preceding embodiments, which is ready-to-use.

-   E15. A process for manufacturing the pharmaceutical aqueous solution    as defined in any one of the preceding E embodiments, comprising the    process steps:    -   (1) Forming a complex of the radionuclide ¹⁷⁷Lu and a        somatostatin receptor binding peptide linked to the chelating        agent DOTA by        -   (1.1) preparing an aqueous solution comprising the            radionuclide;        -   (1.2) preparing an aqueous solution comprising the a            somatostatin receptor binding peptide linked to the            chelating agent, and at least one stabilizer against            radiolytic degradation; and        -   (1.3) mixing the solutions obtained in steps (1.1) and (1.2)            and heating the resulting mixture;    -   (2) Diluting the complex solution obtained by step (1) by        -   (2.1) preparing an aqueous dilution solution optionally            comprising at least one stabilizer against radiolytic            degradation; and        -   (2.2.) mixing the complex solution obtained by step (1) with            the dilution solution obtained by the step (2.1) to obtain            the final solution;    -   wherein if the solution prepared under (1.2) comprises only one        stabilizer, then the solution prepared under (2.1) comprise at        least one stabilizer.

-   E16. The process according to embodiment E15 wherein the solution    prepared in step (1.2) comprises at least one stabilizer and the    solution prepared in step (2.1) comprises at least one stabilizer.

-   E17. The process according to embodiment E15 wherein the solution    prepared in step (1.2) comprises at least the stabilizer gentisic    acid and the solution prepared in step (2.1) comprises at least the    stabilizer ascorbic acid.

-   E18. The process according to embodiment E15 wherein the solution    prepared in step (1.2) comprises only one stabilizer which is    gentisic acid and the solution prepared in step (2.1) comprises only    one stabilizer which is ascorbic acid.

-   E19. The process according to any one of embodiments E15 to E18    wherein the solution prepared in step (1.2) comprises    stabilizer/stabilizers in a total concentration of from 15 to 50    mg/mL, preferably from 20 to 40 mg/mL.

-   E20. The process according to any one of embodiments E15 to E18    wherein the solution prepared in step (1.2) comprises only one    stabilizer which is gentisic acid in a concentration of from 20 to    40 mg/mL, preferably from 25 to 35 mg/mL.

-   E21. The process according any one of embodiments E15 to E20,    wherein the solution of step (1.2) further comprises a buffer,    preferably an acetate buffer.

-   E22. The process according to any one of embodiments E15 to E21,    wherein in step (1.3) the resulting mixture is heated to a    temperature of from 70 to 99° C. (e.g., between 80-99° C.),    preferably from 90 to 98° C. (e.g., 90-95° C.), for from 2 to 59 min    (e.g., 2-20 min, 2-15 min, 5-15 min, or 5-12 min), preferably from    5-15 min or 10 to 15 min.

-   E23. The process according to any one of embodiments E15 to E22,    wherein the solution of step (2.1) further comprises    diethylentriaminepentaacetic acid (DTPA) or a salt thereof.

-   E24. The process according to any one of embodiments E15 to E23,    further comprising the process steps:    -   (3) Filtering the solution obtained by step (2) through 0.2 μm:    -   (4) Dispensing the filtered solution obtained by step (3) into        dose unit containers in a volume required to deliver the        radioactive dose of from 5.0 to 10 MBq, preferably from 7.0 to        8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more        preferably from 7.4-7.5 MBq, preferably said volume is from 10        to 50 mL, more preferably from 15 to 30 mL, even more preferably        from 20 to 25 mL.

-   E25. The process according to any one of embodiments E15 to E24,    wherein the solution of step (1.1) comprises LuCl₃ and HCl.

-   E26. The process according to any one of embodiments E15 to E25,    wherein the solution of step (1.2) comprises ¹⁷⁷Lu-DOTA-TATE or    ¹⁷⁷Lu-DOTA-TOC, gentisic acid, acetic acid, and sodium acetate.

-   E27. The process according to any one of embodiments E15 to E26,    wherein the solution of step (2.1) comprises DTPA, and ascorbic    acid.

-   E28. The process according to any one of embodiments E24 to E27,    wherein the dose unit containers in step (4) are stoppered vials,    enclosed within a lead container.

-   E29. The pharmaceutical aqueous solution obtained (or: obtainable)    by the process as defined by any one of embodiments E15 to E28.

Further embodiments of the present invention are described in thefollowing as “EE embodiments”:

-   EE1. A process for manufacturing a pharmaceutical aqueous solution,    comprising:    -   providing a solution comprising a complex of the radionuclide        ¹⁷⁷Lu (Lutetium-177) and a somatostatin receptor binding peptide        linked to the chelating agent DOTA; a first stabilizer against        radiolytic degradation, and optionally a second stabilizer        against radiolytic degradation different from the first        stabilizer; and    -   diluting the solution comprising the complex with an aqueous        dilution solution optionally comprising at least one stabilizer        against radiolytic degradation to obtain the pharmaceutical        aqueous solution;    -   wherein if the solution comprising the complex comprises only        the first stabilizer and not the second stabilizer, then the        aqueous dilution solution comprises at least one stabilizer that        is different from the first stabilizer, and in the obtained        pharmaceutical aqueous solution, the radionuclide ¹⁷⁷Lu is        present in a concentration that it provides a volumetric        radioactivity of from 250 to 500 MBq/mL and the stabilizers are        present in a total concentration of from 0.2 to 20.0 mg/mL.

For example, the first stabilizer is gentisic acid or a salt thereof andthe second stabilizer, when present, is ascorbic acid or a salt thereof.For example, the at least one stabilizer in the aqueous dilutionsolution, when present, is ascorbic acid or a salt thereof.

-   EE2. The process according to embodiment EE1, comprising the process    steps:    -   (1) forming a complex of the radionuclide ¹⁷⁷Lu and a        somatostatin receptor binding peptide linked to the chelating        agent DOTA by        -   (1.1) providing an aqueous solution comprising the            radionuclide;        -   (1.2) providing an aqueous solution comprising the a            somatostatin receptor binding peptide linked to the            chelating agent, and a first stabilizer against radiolytic            degradation and optionally a second stabilizer against            radiolytic degradation different from the first stabilizer;            and        -   (1.3) mixing the solutions provided in steps (1.1) and (1.2)            and heating the resulting mixture to form a solution            comprising the complex;    -   (2) diluting the solution comprising the complex obtained by        step (1) by        -   (2.1) providing an aqueous dilution solution optionally            comprising at least one stabilizer against radiolytic            degradation; and        -   (2.2.) mixing the solution comprising the complex obtained            by step (1) with the dilution solution provided in step            (2.1) to obtain the pharmaceutical aqueous solution;    -   wherein if the solution in step (1.2) comprises only one        stabilizer that is the first stabilizer, then the solution in        step (2.1) comprise at least one stabilizer that is different        from the first stabilizer.-   EE3. The process according to embodiment EE1 or EE2, wherein the    solution in step (1.2) comprises the first stabilizer and the    solution provided in step (2.1) comprises at least one stabilizer.-   EE4. The process according to any one of embodiments EE1 to EE3,    wherein the solution provided in step (1.2) comprises at least    gentisic acid or a salt thereof and the solution provided in step    (2.1) comprises at least ascorbic acid or a salt thereof.-   EE5. The process according to any one of embodiments EE1 to EE4,    wherein the solution provided in step (1.2) comprises only one    stabilizer which is gentisic acid or a salt thereof and the solution    provided in step (2.1) comprises only one stabilizer which is    ascorbic acid or a salt thereof.-   EE6. The process according to any one of embodiments EE1 to EE5,    wherein the solution provided in step (1.2) comprises    stabilizer/stabilizers in a total concentration of from 15 to 50    mg/mL.-   EE7. The process according to any one of embodiments EE1 to EE6,    wherein the solution provided in step (1.2) comprises    stabilizer/stabilizers in a total concentration of from 20 to 40    mg/mL-   EE8. The process according to any one of embodiments EE1 to EE7,    wherein the solution provided in step (1.2) comprises only one    stabilizer which is gentisic acid in a concentration of from 20 to    40 mg/mL.-   EE9. The process according to any one of embodiments EE1 to EE8,    wherein the solution provided in step (1.2) comprises only one    stabilizer which is gentisic acid in a concentration of from 25 to    35 mg/mL.-   EE10. The process according to any one of embodiments EE1 to EE9,    wherein the solution provided in step (1.2) further comprises a    buffer, e.g., an acetate buffer.-   EE11. The process according to any one of embodiments EE1 to EE10,    wherein in step (1.3) the resulting mixture is heated to a    temperature of from 70 to 99° C. (e.g., between 80-99° C., 90-98°    C., or between 90-95° C.).-   EE12. The process according to any one of embodiments EE1 to EE11,    wherein in step (1.3) the resulting mixture is heated from 2 to 59    min (e.g., 2-20 min, 2-15 min, 5-15 min, 5-12 min, 5-15 min or 10 to    15 min).-   EE13. The process according to any one of embodiments EE1 to EE12,    wherein in step (1.3) the resulting mixture is heated to a    temperature of from 90 to 98° C. for from 10 to 15 min.-   EE14. The process according to any one of embodiments EE1 to EE13,    wherein the solution provided in step (2.1) further comprises    diethylentriaminepentaacetic acid (DTPA) or a salt thereof.-   EE15. The process according to any one of embodiments EE1 to EE14,    further comprising the process steps:    -   (3) filtering the solution obtained by step (2) through 0.2 μm;        and    -   (4) dispensing the filtered solution obtained by step (3) into        dose unit containers in a volume required to deliver the        radioactive dose of from about 5 to about 10 MBq (e.g., from        about 7 to about 8 MBq, or from 7.3 to 7.7 MBq, or from 7.4-7.5        MBq).

For example, the volume in embodiment EE15 is from about 10 to about 50mL, e.g., from about 15 to about 30 mL or from about 20 to about 25 mL.

-   EE16. The process according to any one of embodiments EE1 to EE15,    wherein the solution of step (1.1) comprises LuCl₃ and HCl.-   EE17. The process according to any one of embodiments EE1 to EE16,    wherein the solution of step (1.2) comprises ¹⁷⁷Lu-DOTA-TATE or    ¹⁷⁷Lu-DOTA-TOC, gentisic acid, acetic acid, and sodium acetate.-   EE18. The process according to any one of embodiments EE1 to EE17,    wherein the solution of step (2.1) comprises DTPA and ascorbic acid.-   EE19. The process according to any one of embodiments EE15 to EE18,    wherein the dose unit containers in step (4) are stoppered vials,    enclosed within a lead container.-   EE20. The pharmaceutical aqueous solution obtained (or: obtainable)    by the process as defined by any one of embodiments EE1 to E19.-   EE21. The pharmaceutical aqueous solution according to embodiment    EE20, which has a shelf life of at least 72 h when stored at ≤25°    C., in particular at least 72 h when stored at 25° C.-   EE22. The pharmaceutical aqueous solution according to embodiment    EE20 or EE21, for which the radiochemical purity (determined by    HPLC) is maintained at ≥95% for at least 72 h when stored at 25° C.-   EE23. The pharmaceutical aqueous solution according to any one of    embodiments EE20 to EE22, wherein said solution is produced at a    batch size of at least 20 GBq, at least 50 GBq, or at least 70 GBq.-   EE24. The pharmaceutical aqueous solution according to any one of    embodiments EE20 to EE23, which is ready to use.-   EE25. The pharmaceutical aqueous solution according to any one of    embodiments EE20 to EE24, free of ethanol.-   EE26. The pharmaceutical aqueous solution according to any one of    embodiments EE20 to EE25, wherein gentisic acid is present in a    concentration of from 0.5 to 2 mg/mL, preferably from 0.5 to 1    mg/mL; and ascorbic acid is present in a concentration of from 2.0    to 5.0 mg/mL.-   EE27. The pharmaceutical aqueous solution according to any one of    embodiments EE20 to EE26, wherein the diethylentriaminepentaacetic    acid (DTPA) or a salt thereof is present in a concentration of from    0.01 to 0.10 mg/mL.-   EE28. The pharmaceutical aqueous solution according to any one of    embodiments EE20 to EE27, wherein the acetate buffer is composed of    acetic acid in a concentration of from 0.3 to 0.7 mg/mL; and sodium    acetate in a concentration from 0.4 to 0.9 mg/mL; preferably said    acetate buffer provides for a pH of from 4.5 to 6.0, preferably from    5.0 to 5.5.

In all the embodiments as described herein, the somatostatin receptorbinding peptide linked to the chelating agent DOTA (component (aii)) ispreferably DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), morepreferably DOTA-TATE (oxodotreotide).

The present invention further provides the pharmaceutical aqueoussolution as defined herein for use in the treatment of neuroendocrinetumors (NET).

Alternatively, the present invention provides a method for the treatmentof NET in human patients in need of such treatment which comprisesadministering an effective amount of the pharmaceutical aqueous solutionas defined herein.

As a further alternative the present invention provides the use ofpharmaceutical aqueous solution as defined herein for themanufacture/preparation of a medicament for the treatment of NET.

As a further alternative the present invention provides a medicament forthe treatment of NET comprising pharmaceutical aqueous solution asdefined herein.

Neuroendocrine tumors (NET) which may be treated by the pharmaceuticalaqueous solutions as defined here alone or in combinations in accordancewith the present invention are selected from the group consisting ofgastroenteropancreatic neuroendocrine tumor, carcinoid tumor,pheochromocytoma, paraganglioma, medullary thyroid cancer, pulmonaryneuroendocrine tumor, thymic neuroendocrine tumor, a carcinoid tumor ora pancreatic neuroendocrine tumor, pituitary adenoma, adrenal glandtumors, Merkel cell carcinoma, breast cancer, Non-Hodgkin lymphoma,Hodgkin lymphoma, Head & Neck tumor, urothelial carcinoma (bladder),Renal Cell Carcinoma, Hepatocellular Carcinoma, GIST, neuroblastoma,bile duct tumor, cervix tumor, Ewing sarcoma, osteosarcoma, small celllung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma,medulloblastoma, hemangioblastoma, supratentorial primitive,neuroectodermal tumor, and esthesioneuroblastoma.

Further NET tumors which may be treated by the pharmaceutical aqueoussolutions as defined here alone or in combinations in accordance withthe present invention may be selected from the group consisting offunctional carcinoid tumor, insulinoma, gastrinoma, vasoactiveintestinal peptide (VIP) oma, glucagonoma, serotoninoma, histaminoma,ACTHoma, pheocromocytoma, and somatostatinoma.

The present invention further provides the combination or combinationtherapy of the complex formed by the radionuclide ¹⁷⁷Lu (Lutetium-177),and a somatostatin receptor binding peptide linked to the chelatingagent as defined herein, or the combination or combination therapy ofthe pharmaceutical aqueous solution as defined herein, together with oneof more therapeutic agents as outlined in the following:

In certain instances, pharmaceutical aqueous solution of the presentinvention are combined with other therapeutic agents, such as otheranti-cancer agents, anti-allergic agents, anti-nausea agents (oranti-emetics), pain relievers, cytoprotective agents, and combinationsthereof.

General Chemotherapeutic agents considered for use in combinationtherapies include anastrozole (Arimidex®), bicalutamide (Casodex®),bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection(Busulfex®), capecitabine (Xeloda®),N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®),carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®),cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®),cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposomeinjection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin(Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®),daunorubicin citrate liposome injection (DaunoXome®), dexamethasone,docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®),etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil(Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®),ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine(Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®),mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), phoenix(Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustineimplant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®),6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecanhydrochloride for injection (Hycamptin®), vinblastine (Velban®),vincristine (Oncovin®), and vinorelbine (Navelbine®).

Anti-cancer agents of particular interest for combinations with thepharmaceutical aqueous solution of the present invention include:

Tyrosine kinase inhibitors: Erlotinib hydrochloride (Tarceva®);Linifanib(N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea,also known as ABT 869, available from Genentech); Sunitinib malate(Sutent®); Bosutinib(4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile,also known as SKI-606, and described in U.S. Pat. No. 6,780,996);Dasatinib (Sprycel®); Pazopanib (Votrient®); Sorafenib (Nexavar®);Zactima (ZD6474); and Imatinib or Imatinib mesylate (Gilvec® andGleevec®).

Vascular Endothelial Growth Factor (VEGF) receptor inhibitors:Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate(BMS-582664,(S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate);Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®);Cediranib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®);Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951, CAS475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanibdihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS649735-46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate(AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,described in PCT Publication No. WO 02/066470); Dovitinib dilactic acid(TKI258, CAS 852433-84-2); Linfanib (ABT869, CAS 796967-16-3);Cabozantinib (XL184, CAS 849217-68-1); Lestaurtinib (CAS 111358-88-4);N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide(BMS38703, CAS 345627-80-7);(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol(BMS690514);N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine(XL647, CAS 781613-23-8);4-Methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide(BHG712, CAS 940310-85-0); and Aflibercept (Eylea®), sulfatinib,surufatinib.

Platelet-derived Growth Factor (PDGF) receptor inhibitors: Imatinib(Gleevec®); Linifanib(N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea,also known as ABT 869, available from Genentech); Sunitinib malate(Sutent®); Quizartinib (AC220, CAS 950769-58-1); Pazopanib (Votrient®);Axitinib (Inlyta®); Sorafenib (Nexavar®); Vargatef (BIBF1120, CAS928326-83-4); Telatinib (BAY57-9352, CAS 332012-40-5); Vatalanibdihydrochloride (PTK787, CAS 212141-51-0); and Motesanib diphosphate(AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,described in PCT Publication No. WO 02/066470).

Fibroblast Growth Factor Receptor (FGFR) Inhibitors: Brivanib alaninate(BMS-582664,(S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate);Vargatef (BIBF1120, CAS 928326-83-4); Dovitinib dilactic acid (TKI258,CAS 852433-84-2);3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea(BGJ398, CAS 872511-34-7); Danusertib (PHA-739358); andN-[2-[[4-(Diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)-urea(PD173074, CAS 219580-11-7). sulfatinib, surufatinib.

Aurora kinase inhibitors: Danusertib (PHA-739358);N-[4-[[6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]phenyl]benzamide(ZM447439, CAS 331771-20-1);4-(2-Amino-4-methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl]-2-pyrimidinamine(CYC116, CAS 693228-63-6); Tozasertib (VX680 or MK-0457, CAS639089-54-6); Alisertib (MLN8237);(N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidine-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide)(PF-03814735);4-[[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoicacid (MLN8054, CAS 869363-13-3); Cenisertib (R-763); Barasertib(AZD1152); andN-cyclopropyl-N′-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]-urea(AT9283).

Cyclin-Dependent Kinase (CDK) inhibitors: Aloisine A; Alvocidib (alsoknown as flavopiridol or HMR-1275,2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone,and described in U.S. Pat. No. 5,621,002); Crizotinib (PF-02341066, CAS877399-52-5);2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one,hydrochloride (P276-00, CAS 920113-03-7); Indisulam (E7070); Roscovitine(CYC202);6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one,hydrochloride (PD0332991); Dinaciclib (SCH727965);N-[5-[[(5-tert-Butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide(BMS 387032, CAS 345627-80-7);4-[[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoicacid (MLN8054, CAS 869363-13-3);5-[3-(4,6-Difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine(AG-024322, CAS 837364-57-5);4-(2,6-Dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acidN-(piperidin-4-yl)amide (AT7519, CAS 844442-38-2);4-[2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine(AZD5438, CAS 602306-29-6); Palbociclib (PD-0332991); and(2R,3R)-3[[2-[[3-[[S(R)]—S-cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol(BAY 10000394), ribociclib.

Checkpoint Kinase (CHK) inhibitors: 7-Hydroxystaurosporine (UCN-01);6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine(SCH900776, CAS 891494-63-6);5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acidN—[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8);4-[((3S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one(CHIR 124, CAS 405168-58-3); 7-Aminodactinomycin (7-AAD),Isogranulatimide, debromohymenialdisine;N-[5-Bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N′-(5-methyl-2-pyrazinyl)urea(LY2603618, CAS 911222-45-2); Sulforaphane (CAS 4478-93-7,4-Methylsulfinylbutyl isothiocyanate);9,10,11,12-Tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione(SB-218078, CAS 135897-06-2); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL),and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr); and(αR)-α-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-Cyclohexaneacetamide(PF-0477736).

3-Phosphoinositide-dependent kinase-1 (PDK1 or PDPK1) inhibitors:7-2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]pheny]-acetamide(OSU-03012, CAS 742112-33-0); Pyrrolidine-1-carboxylic acid(3-{5-bromo-4-[2-(1H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)-amide(BX912, CAS 702674-56-4); and4-Dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide (PHT-427, CAS1191951-57-1).

Protein Kinase C (PKC) activators: Bryostatin I (bryo-1) andSotrastaurin (AEB071).

B-RAF inhibitors: Regorafenib (BAY73-4506, CAS 755037-03-7); Tuvizanib(AV951, CAS 475108-18-0); Vemurafenib (Zelboraf®, PLX-4032, CAS918504-65-1);5-[1-(2-Hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydroinden-1-oneoxime (GDC-0879, CAS 905281-76-7);5-[2-[4-[2-(Dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-Inden-1-oneoxime (GSK2118436 or SB590885); (+/−)-Methyl(5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl)carbamate(also known as XL-281 and BMS908662) andN-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide(also known as PLX4720).

C-RAF Inhibitors: Sorafenib (Nexavar®);3-(Dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-benzamide(ZM336372, CAS 208260-29-1); and3-(1-cyano-1-methylethyl)-N-[3-[(3,4-dihydro-3-methyl-4-oxo-6-quinazolinyl)amino]-4-methylphenyl]-benzamide(AZ628, CAS 1007871-84-2).

Human Granulocyte colony-stimulating factor (G-CSF) modulators:Filgrastim (Neupogen®); Sunitinib malate (Sutent®); Pegilgrastim(Neulasta®) and Quizartinib (AC220, CAS 950769-58-1).

RET Inhibitors: Sunitinib malate (Sutent®); Vandetanib (Caprelsa®);Motesanib diphosphate (AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,described in PCT Publication No. WO 02/066470); Sorafenib (BAY 43-9006);Regorafenib (BAY73-4506, CAS 755037-03-7); and Danusertib (PHA-739358).

FMS-like Tyrosine kinase 3 (FLT3) Inhibitors or CD135: Sunitinib malate(Sutent®); Quizartinib (AC220, CAS 950769-58-1);N-[(1-Methyl-4-piperidinyl)methyl]-3-[3-(trifluoromethoxy)phenyl]-Imidazo[1,2-b]pyridazin-6-aminesulfate (SGI-1776, CAS 1173928-26-1); and Vargatef (BIBF1120, CAS928326-83-4).

c-KIT Inhibitors: Pazopanib (Votrient®); Dovitinib dilactic acid(TKI258, CAS 852433-84-2); Motesanib diphosphate (AMG706, CAS857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,described in PCT Publication No. WO 02/066470); Masitinib (Masivet®);Regorafenib (BAY73-4506, CAS 755037-03-7); Tivozanib (AV951, CAS475108-18-0); Vatalanib dihydrochloride (PTK787, CAS 212141-51-0);Telatinib (BAY57-9352, CAS 332012-40-5); Foretinib (GSK1363089, formerlyXL880, CAS 849217-64-7); Sunitinib malate (Sutent®); Quizartinib (AC220,CAS 950769-58-1); Axitinib (Inlyta®); Dasatinib (BMS-345825); andSorafenib (Nexavar®).

Bcr/Abl kinase inhibitors: Imatinib (Gleevec®); Inilotinibhydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib(SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib(PHA-739358), AT9283 (CAS 1133385-83-7); Saracatinib (AZD0530); andN-[2-[(1S,4R)-6-[[4-(Cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalen-1,4-imin-9-yl]-2-oxoethyl]-acetamide(PF-03814735, CAS 942487-16-3).

IGF-1R inhibitors: Linsitnib (OSI-906);[7-[trans-3-[(Azetidin-1-yl)methyl]cyclobutyl]-5-(3-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine(AEW541, CAS 475488-34-7);[5-(3-Benzyloxyphenyl)-7-[trans-3-[(pyrrolidin-1-yl)methyl]cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine(ADW742 or GSK552602A, CAS 475488-23-4);(2-[[3-Bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-propanedinitrile(Tyrphostin AG1024, CAS 65678-07-1);4-[[(2S)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-3-[7-methyl-5-(4-morpholinyl)-1H-benzimidazol-2-yl]-2(1H)-pyridinone(BMS536924, CAS 468740-43-4);4-[2-[4-[[(2S)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-1,2-dihydro-2-oxo-3-pyridinyl]-7-methyl-1H-benzimidazol-5-yl]-1-piperazinepropanenitrile(BMS554417, CAS 468741-42-6);(2S)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro-3-pyridinyl)-2-methyl-2-pyrrolidinecarboxamide(BMS754807, CAS 1001350-96-4); Picropodophyllotoxin (AXL1717); andNordihydroguareacetic acid.

IGF-1R antibodies: Figitumumab (CP751871); Cixutumumab (IMC-A12);Ganitumab (AMG-479); Robatumumab (SCH-717454); Dalotuzumab (MK0646);R1507 (available from Roche); BIIB022 (available from Biogen); andMEDI-573 (available from MedImmune).

MET inhibitors: Cabozantinib (XL184, CAS 849217-68-1); Foretinib(GSK1363089, formerly XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS1000873-98-2);1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(AMG 458); Cryzotinib (Xalkori®, PF-02341066);(3Z)-5-(2,3-Dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one(SU11271);(3Z)—N-(3-Chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl-2-oxoindoline-5-sulfonamide(SU11274);(3Z)—N-(3-Chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonamide(SU11606);6-[Difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]-quinoline(JNJ38877605, CAS 943540-75-8);2-[4-[1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol(PF04217903, CAS 956905-27-4);N-((2R)-1,4-Dioxan-2-ylmethyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide(MK2461, CAS 917879-39-1);6-[[6-(1-Methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]thio]-quinoline(SGX523, CAS 1022150-57-7); and(3Z)-5-[[(2,6-Dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrol-2-yl]methylene]-1,3-dihydro-2H-indol-2-one(PHA665752, CAS 477575-56-7).

Epidermal growth factor receptor (EGFR) inhibitors: Erlotinibhydrochloride (Tarceva®), Gefitnib (Iressa®);N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3″S″)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide,Tovok®); Vandetanib (Caprelsa®); Lapatinib (Tykerb®);(3R,4R)-4-Amino-1-((4-(3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol(BMS690514); Canertinib dihydrochloride (CI-1033);6-[4-[(4-Ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-Pyrrolo[2,3-d]pyrimidin-4-amine(AEE788, CAS 497839-62-0); Mubritinib (TAK165); Pelitinib (EKB569);Afatinib (BIBW2992); Neratinib (HKI-272);N-[4-[[1-[(3-Fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamicacid, (3S)-3-morpholinylmethyl ester (BMS599626);N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine(XL647, CAS 781613-23-8); and4-[4-[[(1R)-1-Phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol(PKI166, CAS 187724-61-4).

EGFR antibodies: Cetuximab (Erbitux®); Panitumumab (Vectibix®);Matuzumab (EMD-72000); Trastuzumab (Herceptin®); Nimotuzumab (hR3);Zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806(mAb-806, CAS 946414-09-1).

mTOR inhibitors: Temsirolimus (Torisel®); Ridaforolimus (formally knownas deferolimus, (1R,2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, and described inPCT Publication No. WO 03/064383); Everolimus (Afinitor® or RAD001);Rapamycin (AY22989, Sirolimus®); Simapimod (CAS 164301-51-3);(5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol(AZD8055);2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one(PF04691502, CAS 1013101-36-4);N²-[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-,inner salt (SF1126, CAS 936487-67-1); andN-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-benzamide(XL765, also known as SAR245409); and(1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylicacid (OSI-027).

Mitogen-activated protein kinase (MEK) inhibitors: XL-518 (also known asGDC-0973, Cas No. 1029872-29-4, available from ACC Corp.); Selumetinib(5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide,also known as AZD6244 or ARRY 142886, described in PCT Publication No.WO2003077914);2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide(also known as 01-1040 or PD184352 and described in PCT Publication No.WO2000035436);N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide(also known as PD0325901 and described in PCT Publication No.WO2002006213);2,3-Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also knownas U0126 and described in U.S. Pat. No. 2,779,780);N-[3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide(also known as RDEA119 or BAY869766 and described in PCT Publication No.WO2007014011);(3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known asE6201 and described in PCT Publication No. WO2003076424);2′-Amino-3′-methoxyflavone (also known as PD98059 available from BiaffinGmbH & Co., KG, Germany); Vemurafenib (PLX-4032, CAS 918504-65-1);(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(TAK-733, CAS 1035555-63-5); Pimasertib (AS-703026, CAS 1204531-26-9);Trametinib dimethyl sulfoxide (GSK-1120212, CAS 1204531-25-80);2-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide(AZD 8330); and3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655).

Alkylating agents: Oxaliplatin (Eloxatin®); Temozolomide (Temodar® andTemodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®);Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard,Alkeran®); Altretamine (also known as hexamethylmelamine (HMM),Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan(Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (alsoknown as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® andPlatinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® andNeosar®); Dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine(HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine(Matulane®); Mechlorethamine (also known as nitrogen mustard, mustineand mechloroethamine hydrochloride, Mustargen®); Streptozocin(Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA,Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®,Revimmune®); and Bendamustine HCl (Treanda®).

Aromatase inhibitors: Exemestane (Aromasin®); Letrozole (Femara®); andAnastrozole (Arimidex®).

Topoisomerase I inhibitors: Irinotecan (Camptosar®); Topotecanhydrochloride (Hycamtin®); and 7-Ethyl-10-hydroxycampothecin (SN38).

Topoisomerase II inhibitors: Etoposide (VP-16 and Etoposide phosphate,Toposar®, VePesid® and Etopophos®); Teniposide (VM-26, Vumon®); andTafluposide.

DNA Synthesis inhibitors: Capecitabine (Xeloda®); Gemcitabinehydrochloride (Gemzar®); Nelarabine((2R,3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol,Arranon® and Atriance®); and Sapacitabine(1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-4-(palmitoylamino)pyrimidin-2(1H)-one).

Folate Antagonists or Antifolates: Trimetrexate glucuronate(Neutrexin®); Piritrexim isethionate (BW201U); Pemetrexed (LY231514);Raltitrexed (Tomudex®); and Methotrexate (Rheumatrex®, Trexal®).

Immunomodulators: Afutuzumab (available from Roche®); Pegfilgrastim(Neulasta®); Lenalidomide (CC-5013, Revlimid®); Thalidomide (Thalomid®),Actimid (CC4047); and IRX-2 (mixture of human cytokines includinginterleukin 1, interleukin 2, and interferon γ, CAS 951209-71-5,available from IRX Therapeutics).

G-Protein-coupled Somatostain receptors Inhibitors: Octreotide (alsoknown as octreotide acetate, Sandostatin® and Sandostatin LAR®);Lanreotide acetate (CAS 127984-74-1); Seglitide (MK678); Vapreotideacetate (Sanvar®); and Cyclo(D-Trp-Lys-Abu-Phe-MeAla-Tyr)(BIM23027).

Interleukin-11 and Synthetic Interleukin-11 (IL-11): Oprelvekin(Neumega®).

Erythropoietin and Synthetic erythropoietin: Erythropoietin (Epogen® andProcrit®); Darbepoetin alfa (Aranesp®); Peginesatide (Hematide®); andEPO covalently linked to polyethylene glycol (Micera®).

Histone deacetylase (HDAC) inhibitors: Voninostat (Zolinza®); Romidepsin(Istodax®); Treichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®,Suberoylanilide hydroxamic acid); Pyroxamide (syberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B(RF-10238);Cyclo[(aS,2S)-α-amino-q-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl](Cyl-1);Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl](Cyl-2);Cyclic[L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxiraneoctanoyl-D-prolyl](HC-toxin);Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl](WF-3161); Chlamydocin((S)-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxiraneoctanoyl);Apicidin(Cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl);Romidepsin (Istodax®, FR-901228); 4-Phenylbutyrate; Spiruchostatin A;Mylproin (Valproic acid); Entinostat (MS-275,N-(2-Aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-amino-methyl]-benzamide);and Depudecin(4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-Undeca-1,6-dienitol).

Biologic response modifiers: Include therapeutics such as interferons,interleukins, colony-stimulating factors, monoclonal antibodies,vaccines (therapeutic and prophylactic), gene therapy, and nonspecificimmunomodulating agents. Interferon alpha (Intron®, Roferson®-A);Interferon beta; Interferon gamma; Interleukin-2 (IL-2 or aldesleukin,Proleukin®); Filgrastim (Neupogen®); Sargramostim (Leukine®);Erythropoietin (epoetin); Interleukin-11 (oprelvekin); Imiquimod(Aldara®); Lenalidomide (Revlimid®); Rituximab (Rituxan®); Trastuzumab(Herceptin®); Bacillus calmette-guerin (theraCys® and TICE® BCG);Levamisole (Ergamisol®); and Denileukin diftitox (Ontak®).

Plant Alkaloids: Paclitaxel (Taxol and Onxal™); Paclitaxel protein-bound(Abraxane®); Vinblastine (also known as vinblastine sulfate,vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); Vincristine (alsoknown as vincristine sulfate, LCR, and VCR, Oncovin® and Vincasar Pfs®);and Vinorelbine (Navelbine®).

Taxane anti-neoplastic agents: Paclitaxel (Taxol®); Docetaxel(Taxotere®); Cabazitaxel (Jevtana®,1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate);and Larotaxel((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-ylbenzoate).

Heat Shock Protein (HSP) inhibitors: Tanespimycin(17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and17-AAG, available from SIGMA, and described in U.S. Pat. No. 4,261,989);Retaspimycin (IPI504), Ganetespib (STA-9090);[6-Chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-yl]amine(BIIB021 or CNF2024, CAS 848695-25-0);trans-4[[2-(Aminocarbonyl)-5-[4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]amino]cyclohexylglycine ester (SNX5422 or PF04929113, CAS 908115-27-5); and17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).

Thrombopoietin (TpoR) agonists: Eltrombopag (SB497115, Promacta® andRevolade®); and Romiplostim (Nplate®).

Demethylating agents: 5-Azacitidine (Vidaza®); and Decitabine(Dacogen®).

Cytokines: Interleukin-2 (also known as aldesleukin and IL-2,Proleukin®); Interleukin-11 (also known as oprevelkin, Neumega®); andAlpha interferon alfa (also known as IFN-alpha, Intron® A, andRoferon-A®).

17 α-hydroxylase/C17,20 lyase (CYP17A1) inhibitors: Abiraterone acetate(Zyitga®). Miscellaneous cytotoxic agents: Arsenic trioxide (Trisenox®);Asparaginase (also known as L-asparaginase, Erwinia L-asparaginase,Elspar® and Kidrolase®); and Asparaginase Erwinia Chrysanthemi(Erwinaze®).

C—C Chemokine receptor 4 (CCR4) Antibody: Mogamulizumab (Potelligent®)

CD20 antibodies: Rituximab (Riuxan® and MabThera®); and Tositumomab(Bexxar®); and Ofatumumab (Arzerra®).

CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (Zevalin®); andTositumomab,

CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred toas CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co.,Ltd.)

CD30 mAb-cytotoxin Conjugates: Brentuximab vedotin (Adcetrix®);

CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (Mylotarg®),

CD40 antibodies: Dacetuzumab (also known as SGN-40 or huS2C6, availablefrom Seattle Genetics, Inc),

CD52 antibodies: Alemtuzumab (Campath®),

Anti-CS1 antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3)

CTLA-4 inhibitor antibodies: Tremelimumab (IgG2 monoclonal antibodyavailable from Pfizer, formerly known as ticilimumab, CP-675,206); andIpilimumab (CTLA-4 antibody, also known as MDX-010, CAS No.477202-00-9).

TPH inhibitors: telotristat

PARP (poly ADP ribose polymerase) inhibitors: olaparib (Lynparza),rucaparib (Rubraca), Niraparib (Zeluja), Talazoparib, Veliparib.

PD-1 Inhibitors: Spartalizumab (PDR001, Novartis), Nivolumab(Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab(CureTech), MED10680 (Medimmune), REGN2810 (Regeneron), TSR-042(Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene),INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

PD-L1 inhibitors: Durvalumab, Atezolizumab, Avelumab

In particular, the present invention provides the combination orcombination therapy of the complex formed by the radionuclide ¹⁷⁷Lu(Lutetium-177), and a somatostatin receptor binding peptide linked tothe chelating agent as defined herein, or the combination or combinationtherapy of the pharmaceutical aqueous solution as defined herein,together with one of more therapeutic agents selected from the groupconsisting of octreotide, lanreotide, vaproreotide, pasireotide,satoreotide, everolimus, temozolomide, telotristat, sunitinib,sulfatinib, ribociclib, entinostat, and pazopanib. In particularembodiments, those combinations are for use in the treatment of NETtumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome,SCLC. In particular embodiments, the invention provides a method oftreating a patient with NET tumors, e.g. GEP-NET, pulmonary NET, pNET,lung NET, Carcinoid syndrome, SCLC, by administering a therapeuticallyeffective amount of the components of those combinations.

In particular embodiments, the present invention provides thecombination or combination therapy of the complex formed by theradionuclide ¹⁷⁷Lu (Lutetium-177), and a somatostatin receptor bindingpeptide linked to the chelating agent as defined herein, or thecombination or combination therapy of the pharmaceutical aqueoussolution as defined herein, together with one of more immuno-oncologytherapeutic agents selected from the group consisting of PD-1, PD-L1 andCTLA-4 inhibitors, in particular the 1-O therapeutic agents selectedfrom Spartalizumab, Nivolumab, Pembrolizumab, Pidilizumab, Durvalumab,Atezolizumab, Avelumab, Ipilimumab, and Tremelimumab. In particularembodiments, those combinations are for use in the treatment of NETtumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome,SCLC. In particular embodiments, the invention provides a method oftreating a patient with NET tumors, e.g. GEP-NET, pulmonary NET, pNET,lung NET, Carcinoid syndrome, SCLC, by administering a therapeuticallyeffective amount of the components of those combinations.

Definitions

In the following, terms as used herein are defined in their meaning.

The use of the articles “a”, “an”, and “the” in both the description andclaims are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.The terms “comprising”, “having”, “being of” as in e.g., a complex “of aradionuclide and a cell receptor binding organic moiety linked to achelating agent”, “including”, and “containing” are to be construed asopen terms (i.e., meaning “including but not limited to”) unlessotherwise noted. Additionally, whenever “comprising” or anotheropen-ended term is used in an embodiment, it is to be understood thatthe same embodiment can be more narrowly claimed using the intermediateterm “consisting essentially of” or the closed term “consisting of”.

The term “about” or “ca.” has herein the meaning that the followingvalue may vary for ±20%, preferably ±10%, more preferably ±5%, even morepreferably ±2%, even more preferably ±1%.

Unless otherwise defined, “%” has herein the meaning of weight percent(wt %), also referred to as weight by weight percent (w/w %).

“total concentration”: sum of one or more individual concentrations.

“aqueous solution”: a solution of one or more solute in water.

“complex formed by

-   -   (ai) a radionuclide, and    -   (aii) a cell receptor binding organic moiety linked to a        chelating agent”:

-   The radionuclide metal ion is forming a non-covalent bond with the    functional groups of the chelating agent, e.g. amines or carboxylic    acids. The chelating agent has at least two such complexing    functional groups to be able to form a chelate complex.

The chelating agent in the context of the present invention may be

DOTA: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid,

DTPA: Diethylentriaminepentaacetic acid,

NTA: Nitrilotriacetic acid,

EDTA: Ethylenediaminetetraacetic acid,

DO3A: 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid,

NOTA: 1,4,7-Triazacyclononane-1,4,7-triacetic acid,

Trizoxetan,

Tetraxetan

or mixtures thereof, preferably is DOTA.

-   “cell receptor binding moiety”: a chemical molecule which binds with    at least part of its molecule to a receptor molecule at the surface    of a cell. A cell receptor binding moiety, for which the present    invention is in particular suitable, is a somatostatin receptor    binding peptide, preferably said somatostatin receptor binding    peptide is selected from octreotide, octreotate, lanreotide,    vapreotide, pasireotide, ilatreotide, pentetreotide, depreotide,    satoreotide, veldoreotide, preferably selected from octreotide and    octreotate.-   “linked”: the cell receptor binding organic moiety is either    directly linked to the chelating agent or connected via a linker    molecule, preferably it is directly linked. The linking bond(s) is    (are) either covalent or non-covalent bond(s) between the cell    receptor binding organic moiety (and the linker) and the chelating    agent, preferably the bond(s) is (are) covalent.-   “Stabilizer against radiolytic degradation”: stabilizing agent which    protects organic molecules against radiolytic degradation, e.g. when    a gamma ray emitted from the radionuclide is cleaving a bond between    the atoms of an organic molecules and radicals are formed, those    radicals are then scavenged by the stabilizer which avoids the    radicals undergoing any other chemical reactions which might lead to    undesired, potentially ineffective or even toxic molecules.    Therefore, those stabilizers are also referred to as “free radical    scavengers” or in short “radical scavengers”. Other alternative    terms for those stabilizers are “radiation stability enhancers”,    “radiolytic stabilizers”, or simply “quenchers”.-   “stabilizer(s) is (are) present in the solution during the complex    formation of components (ai) and (aii)”: first stabilizer present    and optionally also second stabilizer present, i.e. either first    stabilizer alone or in combination with second stabilizer present-   “present during the complex formation”: stabilizer(s) are in either    the radionuclide solution or in the chelating agent containing    solution before those two solutions are added and potentially    elevated temperatures are applied to facilitate the complex    formation. Preferably the stabilizer(s) are in the chelating agent    containing solution.-   “only the first stabilizer is present during the complex formation    of components (ai) and (aii)”: the first stabilizer is present, the    second is not present. In other words only one stabilizer is    present.-   “second stabilizer is added after the complex formation of    components (ai) and (aii)”: Regardless of whether the second    stabilizers may have been present already during the complex    formation or not, the second stabilizer is added after the complex    forming reaction is completed, e.g. after the reacting solution    which might have been heated up to an elevated temperature is again    cooled down to ambient temperature.-   The cell receptor binding moiety and the chelating agent may form    together the following molecules:-   DOTA-OC: [DOTA⁰ ,D-Phe¹]octreotide,-   DOTA-TOC: [DOTA⁰ ,D-Phe¹,Tyr³]octreotide, edotreotide (INN),

represented by the following formulas:

-   DOTA-NOC: [DOTA⁰ ,D-Phe¹,1-Nal³]octreotide,-   DOTA-TATE: [DOTA⁰ ,D-Phe¹,Tyr³]octreotate, DOTA-Tyr³-Octreotate,    DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo 2,7), oxodotreotide    (INN), represented by the following formula:

-   DOTA-LAN: [DOTA⁰ ,D-β-Nal¹]lanreotide,-   DOTA-VAP: [DOTA⁰ ,D-Phe¹,Tyr³]vapreotide.-   Satoreotide trizoxetan

-   Satoreotide tetraxetan

-   The preferred “cell receptor binding moiety linked to the chelating    agent” molecules for the present invention are DOTA-TOC, DOTA-TATE,    and Satoreotide tetraxetan, more preferably the molecule is    DOTA-TATE.-   For the present invention, the preferred complex formed by (or the    preferred complex of) the radionuclide and the cell receptor binding    moiety linked to the chelating agent according to the present    invention is ¹⁷⁷Lu-DOTA-TATE, which is also referred to as Lutetium    (177Lu) oxodotreotide (INN), i.e. hydrogen    [N-{[4,7,10-tris(carboxylato-κO-methyl)-1,4,7,10-tetraazacyclododecan-1-yl-κ⁴N¹,N⁴,N⁷,N¹⁰]acetyl-κO}-D-phenylalanyl-L-cysteinyl-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoninato    cyclic (2→7)-disulfide(4-)](177Lu)lutetate(1-)    and is represented by the following formulas:

-   “Buffer for a pH from 4.5 to 6.0”: may be an acetate buffer, citrate    buffer (e.g. citrate+HCl or citric acid+Disodium hydrogenphosphate)    or phosphate buffer (e.g. Sodium dihydrogenphosphate+Disodium    hydrogenphosphate), preferably said buffer is an acetate buffer,    preferably said acetate buffer is composed of acetic acid and sodium    acetate.-   “Sequestering agent”, a chelating agent suitable to complex the    radionuclide metal ions, preferably DTPA:    Diethylentriaminepentaacetic acid.-   “for commercial use”: the drug product, e.g. a pharmaceutical    aqueous solution, is able to obtain (preferably has obtained)    marketing authorization by health authorities, e.g. US-FDA or EMA,    by complying with all drug product quality and stability    requirements as demanded by such health authorities, is able to be    manufactured (preferably is manufactured) from or at a    pharmaceutical production site at commercial scale followed by a    quality control testing procedure, and is able to be supplied    (preferably is supplied) to remotely located end users, e.g.    hospitals or patients.

“Combination”: refers to either a fixed combination in one dosage unitform, or a combined administration where a compound of the presentinvention and a combination partner (e.g. another drug as explainedbelow, also referred to as “therapeutic agent” or “co-agent”) may beadministered independently at the same time or separately within timeintervals, especially where these time intervals allow that thecombination partners show a cooperative, e.g. synergistic effect. Thesingle components may be packaged in a kit or separately. One or both ofthe components (e.g., powders or liquids) may be reconstituted ordiluted to a desired dose prior to administration. The terms“co-administration” or “combined administration” or the like as utilizedherein are meant to encompass administration of the selected combinationpartner to a single subject in need thereof (e.g. a patient), and areintended to include treatment regimens in which the agents are notnecessarily administered by the same route of administration or at thesame time. The term “pharmaceutical combination” as used herein means aproduct that results from the mixing or combining of more than onetherapeutic agent and includes both fixed and non-fixed combinations ofthe therapeutic agents. The term “fixed combination” means that thetherapeutic agents, e.g. a compound of the present invention and acombination partner, are both administered to a patient simultaneouslyin the form of a single entity or dosage. The term “non-fixedcombination” means that the therapeutic agents, e.g. a compound of thepresent invention and a combination partner, are both administered to apatient as separate entities either simultaneously, concurrently orsequentially with no specific time limits, wherein such administrationprovides therapeutically effective levels of the two compounds in thebody of the patient. The latter also applies to cocktail therapy, e.g.the administration of three or more therapeutic agent.

EXAMPLES

Hereinafter, the present invention is described in more details andspecifically with reference to the examples, which however are notintended to limit the present invention.

Materials:

The ¹⁷⁷LuCl₃ may be obtained from commercial sources, e.g. I.D.B.Holland BV. The DOTA⁰-Tyr³-Octreotate may be obtained from commercialsources, e.g. by piCHEM Forschungs- and Entwicklungs GmbH, Austria. Allother components of the drug product are commercially available fromvarious sources.

Example 1: Composition of Drug Product

The Drug Product (¹⁷⁷Lu-DOTA⁰-Tyr³-Octreotate 370 MBq/mL solution forinfusion) is designed as a sterile ready-to-use solution for infusioncontaining ¹⁷⁷Lu-DOTA⁰-Tyr³-Octreotate as Drug Substance with avolumetric activity of 370 MBq/mL at reference date and time(calibration time (tc)). Calibration time (tc) corresponds to the End ofProduction (EOP=t0) which is the time of measurement of the activity ofthe first QC vial. The shelf-life of Drug Product is defined as 72 hoursafter calibration time. Drug Product is a single dose vial, containingsuitable amount of solution that allows delivery of 7.4 GBq ofradioactivity at injection time.

Manufacturing site prepares single doses calibrated within the range of7.4 GBq±10% (200 mCi) after the end of production. Certificates ofanalysis reports both the exact activity provided and the time when thisactivity is reached. This value is declared as “Injection time: {DD MMYYYY} {hh:mm} UTC”. Considering the variable injection time and constantdecay of the radionuclide, the filling volume needed for an activity of7.4 GBq at injection time is calculated and can range from 20.5 and 25.0mL.

Composition of Drug Product Per mL

Property/Component Quantity (Unit/mL) Function¹⁷⁷Lu-DOTA⁰-Tyr³-Octreotate 370 MBq/mL at t_(c) (EOP) Drug Substance(volumetric activity) X-DOTA⁰-Tyr³-Octreotate 10 μg/mL Total peptidecontent Specific Activity ≥53 GBq/μmol at EOP NA (GBq/Total peptide)Excipients Acetic acid 0.48 mg/mL pH adjuster Sodium acetate 0.66 mg/mLpH adjuster Gentisic acid 0.63 mg/mL RSE Ascorbic acid 2.80 mg/mL RSEDTPA 0.05 mg/mL Sequestering agent Sodium chloride (NaCl) 6.85 mg/mLIsotonizing agent Sodium hydroxide (NaOH) 0.64 mg/mL pH adjuster Waterfor injection Ad 1 mL Solvent EOP: End of Production = t₀ = activitymeasurement of the first vial = calibration time t_(c) RSE: RadiationStability Enhancer

Example 2: Manufacturing of Drug Product

For a 74 GBq batch size (2 Ci batch size) a ¹⁷⁷LuCl₃ solution, about 74GBq in HCl, is mixed together with a DOTA-Tyr³-Octreotate (about 2 mg)solution, and a Reaction Buffer solution, containing an antioxidantagent (and stabilizator against radiolytic regradation) (i.e. Gentisicacid, about 157 mg) and a buffer system (i.e. Acetate buffer system),resulting in a total of about 5.5 mL solution, which is used forradiolabelling that occurs at a temperature of about 90 to about 98° C.within less than 15 minutes.

The synthesis is carried out using a single use disposable kit cassetteinstalled on the front of the synthesis module which contains the fluidpathway (tubing), reactor vial and sealed reagent vials.

The obtained mother solution is diluted with a solution containing achelating agent (i.e. DTPA), an antioxidant agent (i.e. Ascorbic acid)sodium hydroxide, and sodium chloride and, then sterile filtered through0.2 μm to give the ready-to-use solution as described in Example 1 witha pH of 4.5-6.0, in particular 5.2-5.3. Finally, the solution isdispensed in volumes of from 20.5 to 25.0 mL into sterile vials. Thestoppered vials are enclosed within lead containers for protectiveshielding.

Manufacturing Process can also be implemented for batch sizes higherthan 74 GBq. In this case the amount of the raw materials (Lutetium,peptide and Reaction Buffer) are multiplied to guarantee the same rawmaterials ratio.

Example 3: Stability Study Results after Storage at Various TemperatureConditions

The following table provides the stability test data for a batchproduced at 74 GBq batch size according to the process described inExample 2.

Time points t(0 + 72 h) t(0) 11 mL Stability at 5 ± 2° C. CQ1 t(0 + 24h) t(0 + 48 h) 21.8 mL pH 5.3 n.d. n.d. 5.3 5.3 Chemical purity Peptidepurity (%) 100.0 n.d. n.d. 100.0 (RP-UV-HPLC) 100.0 Radiochemical¹⁷⁷Lu-DOTA⁰- 98.37 n.d. n.d. 96.09 purity Tyr³-octreotate (%) 96.40(RP-γβ-HPLC) Time points t(0 + 72 h) t(0) t(0 + 24 h) t(0 + 48 h) 5 mLStability at 25 ± 2° C. CQ1 5 mL 5mL 24.7 mL pH 5.3 5.3 5.2 5.2 5.3Chemical purity Peptide purity (%) 100.0 100.0 100.0 100.0 (RP-UV-HPLC)Radiochemical ¹⁷⁷Lu-DOTA⁰- 98.28 96.99 96.29 95.02 purityTyr³-octreotate (%) 95.62 (RP-γβ-HPLC) Time points t(0 + 24 h) t(0 + 48h) t(0) 5.6 mL 5.6 mL Stability at 32 ± 2° C. CQ1 22.2 mL 22.2 mL t(0 +72 h) pH 5.3 n.d. 5.3 n.d. 5.3 Chemical purity Peptide purity (%) 100.0100.0 100.0 n.d. (RP-UV-HPLC) 100.0 100.0 Radiochemical ¹⁷⁷Lu-DOTA⁰-98.37 96.03 94.45 n.d. purity Tyr³-octreotate (%) 96.51 95.45(RP-γβ-HPLC) Time points Stability at 32 ± 2° C. per 12 h t(0) t(0 + 72h) and at 25 ± 2° C. per 60 h CQ1 t(0 + 24 h) t(0 + 48 h) 11 mL Chemicalpurity Peptide purity (%) 100.0 n.d. n.d. 100.0 (RP-UV-HPLC)Radiochemical ¹⁷⁷Lu-DOTA⁰- 98.28 n.d. n.d. 95.01 purity Tyr³-octreotate(%) (RP-γβ-HPLC) “n.d.” = not determined; “LOD” = limit of detection

Very similar good stability results were obtained for batches producedat 148 GBq batch size.

1. A process for manufacturing a pharmaceutical aqueous solution,comprising: providing a solution comprising a complex of theradionuclide ¹⁷⁷Lu (Lutetium-177) and a somatostatin receptor bindingpeptide linked to the chelating agent DOTA; a first stabilizer againstradiolytic degradation, and optionally a second stabilizer againstradiolytic degradation different from the first stabilizer; and dilutingthe solution comprising the complex with an aqueous dilution solutionoptionally comprising at least one stabilizer against radiolyticdegradation to obtain the pharmaceutical aqueous solution; wherein ifthe solution comprising the complex comprises only the first stabilizerand not the second stabilizer, then the aqueous dilution solutioncomprises at least one stabilizer that is different from the firststabilizer, and in the obtained pharmaceutical aqueous solution, theradionuclide ¹⁷⁷Lu is present in a concentration that it provides avolumetric radioactivity of from 250 to 500 MBq/mL and the stabilizersare present in a total concentration of from 0.2 to 20.0 mg/m L.
 2. Theprocess according to claim 1, comprising: (1) forming a complex of theradionuclide ¹⁷⁷Lu and a somatostatin receptor binding peptide linked tothe chelating agent DOTA by (1.1) providing an aqueous solutioncomprising the radionuclide; (1.2) providing an aqueous solutioncomprising the a somatostatin receptor binding peptide linked to thechelating agent, and a first stabilizer against radiolytic degradationand optionally a second stabilizer against radiolytic degradationdifferent from the first stabilizer; and (1.3) mixing the solutionsprovided in steps (1.1) and (1.2) and heating the resulting mixture toform a solution comprising the complex; (2) diluting the solutioncomprising the complex obtained by step (1) by (2.1) providing anaqueous dilution solution optionally comprising at least one stabilizeragainst radiolytic degradation; and (2.2.) mixing the solutioncomprising the complex obtained by step (1) with the dilution solutionprovided in step (2.1) to obtain the pharmaceutical aqueous solution;wherein if the solution in step (1.2) comprises only one stabilizer thatis the first stabilizer, then the solution in step (2.1) comprise atleast one stabilizer that is different from the first stabilizer.
 3. Theprocess according to claim 2, wherein the solution in step (1.2)comprises the first stabilizer and the solution provided in step (2.1)comprises at least one stabilizer.
 4. The process according to claim 2,wherein the solution provided in step (1.2) comprises at least gentisicacid or a salt thereof and the solution provided in step (2.1) comprisesat least ascorbic acid or a salt thereof.
 5. The process according toclaim 2, wherein the solution provided in step (1.2) comprises only onestabilizer which is gentisic acid or a salt thereof and the solutionprovided in step (2.1) comprises only one stabilizer which is ascorbicacid or a salt thereof.
 6. The process according to claim 2, wherein thesolution provided in step (1.2) comprises stabilizer/stabilizers in atotal concentration of from 15 to 50 mg/mL.
 7. The process according toclaim 6, wherein the solution provided in step (1.2) comprisesstabilizer/stabilizers in a total concentration of from 20 to 40 mg/mL8. The process according to claim 7, wherein the solution provided instep (1.2) comprises only one stabilizer which is gentisic acid in aconcentration of from 20 to 40 mg/m L.
 9. The process according to claim8, wherein the solution provided in step (1.2) comprises only onestabilizer which is gentisic acid in a concentration of from 25 to 35mg/m L.
 10. The process according to claim 9, wherein the solutionprovided in step (1.2) further comprises a buffer.
 11. The processaccording to claim 10, wherein the buffer is an acetate buffer.
 12. Theprocess according to claim 2, wherein in step (1.3) the resultingmixture is heated to a temperature of from 70 to 99° C., for from 2 to59 min.
 13. The process according to claim 12, wherein in step (1.3) theresulting mixture is heated to a temperature of from 90 to 98° C. forfrom 5 to 15 min.
 14. The process according to claim 2, wherein thesolution provided in step (2.1) further comprisesdiethylentriaminepentaacetic acid (DTPA) or a salt thereof.
 15. Theprocess according to claim 2, further comprising the process steps: (3)filtering the solution obtained by step (2) through 0.2 μm; and (4)dispensing the filtered solution obtained by step (3) into dose unitcontainers in a volume required to deliver the radioactive dose of from5.0 to 10 MBq.
 16. The process according to claim 2, wherein thesolution of step (1.1) comprises LuCl₃ and HCl.
 17. The processaccording to claim 2, wherein the solution of step (1.2) comprises¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC, gentisic acid, acetic acid, andsodium acetate.
 18. The process according to claim 2, wherein thesolution of step (2.1) comprises DTPA and ascorbic acid.
 19. The processaccording to claim 15, wherein the dose unit containers in step (4) arestoppered vials, enclosed within a lead container.
 20. Thepharmaceutical aqueous solution obtained by the process of claim
 1. 21.The pharmaceutical aqueous solution according to claim 20, which is freeof ethanol.
 22. The process according to claim 1, comprising: providinga solution comprising a complex of the radionuclide ¹⁷⁷Lu (Lutetium-177)and a somatostatin receptor binding peptide linked to the chelatingagent DOTA; a first stabilizer against radiolytic degradation, andoptionally a second stabilizer against radiolytic degradation differentfrom the first stabilizer; and diluting the solution comprising thecomplex with an aqueous dilution solution comprising at least onestabilizer against radiolytic degradation to obtain the pharmaceuticalaqueous solution; wherein if the solution comprising the complexcomprises only the first stabilizer as an stabilizer against radiolyticdegradation and not the second stabilizer, then the aqueous dilutionsolution comprises at least one stabilizer against radiolyticdegradation that is different from the first stabilizer, and in theobtained pharmaceutical aqueous solution, the radionuclide ¹⁷⁷Lu ispresent in a concentration that it provides a volumetric radioactivityof from 250 to 500 MBq/mL, the stabilizers are present in a totalconcentration of from 1.0 to 5.0 mg/mL, and ethanol is present in aconcentration of less than 1%.
 23. The pharmaceutical aqueous solutionobtained by the process of claim
 22. 24. The pharmaceutical aqueoussolution according to claim 23, wherein the stabilizers in the obtainedpharmaceutical aqueous solution consists essentially of gentisic acid ora salt thereof and ascorbic acid or a salt thereof.
 25. Thepharmaceutical aqueous solution according to claim 23, wherein thestabilizers are present in a total concentration of from about 2.7 toabout 4.1 mg/mL.
 26. The pharmaceutical aqueous solution according toclaim 23, for which the radiochemical purity (determined by HPLC) ismaintained at ≥95% for at least 72 h when stored at 25° C.